Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history

Cancer. 2001 Aug 1;92(3):479-87. doi: 10.1002/1097-0142(20010801)92:3<479::aid-cncr1346>;2-g.


Background: An increased incidence of breast carcinoma has been reported among relatives of individuals who are affected with the rare recessive disorder, ataxia-telangiectasia (A-T), and who are heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. However, most studies of breast carcinoma cases from the general population have failed to find a higher incidence of ATM mutations in cases when compared with controls.

Methods: Genomic DNA samples from 258 individuals were screened for mutations of all types in each of the 62 coding exons of the ATM gene; 142 of these were from breast carcinoma cases with a first-degree family history or early age at diagnosis, 35 were from cases selected for the presence of either known disease-related mutations (n = 25) or missense alterations of unknown consequences (n = 10) in BRCA1 or BRCA2, and 81 were from matched controls.

Results: A total of 12 individuals with ATM mutations were identified, 11 among 142 breast carcinoma cases (7.7%; 95% CI, 3.9-13.4%) and 1 among 81 controls (1.2%; 95% CI, 0.0-6.7%) (P = 0.06). All mutations detected were of the missense type; none were predicted to truncate the ATM protein. Among cases, mutations were found exclusively in patients with a family history of breast carcinoma (12.1%; 95% CI, 6.2-20.6%) (P = 0.02). Similar frequencies of ATM mutations were found in 35 additional cases selected for the presence of BRCA1 or BRCA2 mutations when compared with cases overall.

Conclusions: ATM mutations, specifically missense mutations, are more common in breast carcinoma cases selected for first-degree family history and early age at diagnosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / genetics
  • BRCA2 Protein
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / physiopathology
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Exons / genetics
  • Family Health
  • Female
  • Gene Frequency
  • Genetic Markers / genetics
  • Humans
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Risk Factors
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins


  • BRCA1 Protein
  • BRCA2 Protein
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Genetic Markers
  • Neoplasm Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases